High gas barrier receptacle and closure assembly

ABSTRACT

The present invention provides a receptacle for a therapeutic fluid susceptible to deterioration on exposure to a gas such as oxygen or carbon dioxide. The receptacle has walls of sheet material each including at least one layer forming a barrier essentially impermeable to such gas, and a seal sealing the walls together in a region thereof. A transfer tube is sealed in the seal having a proximal end in the receptacle, a distal end accessible from outside the receptacle, a flow passage extending between said proximal and distal ends, and a closure blocking flow through the flow passage adapted to be pierced by a tubular needle for transfer of therapeutic through the needle. The transfer tube and closure are essentially impermeable to said gas.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of provisional application Ser. No.60/284,277, filed Apr. 17, 2001, which is incorporated by reference andmade a part hereof.

TECHNICAL FIELD

The present invention relates to a high gas barrier primary receptaclesystem, and more particularly to a receptacle system for medicalsolutions.

BACKGROUND OF THE INVENTION

There is an ever increasing number of therapeutic fluids being developedfor delivery by a flexible receptacle. Many of these therapeutic fluidsare sensitive as they degrade or react with gases such as oxygen andcarbon dioxide. These therapeutic fluids must be protected from contactby such gases to maintain the efficacy of the therapeutic fluid.

For example, hemoglobin solutions are known to lose their ability tofunction as blood substitutes during storage. A hemoglobin solutionloses its ability to function as a blood substitute because ofspontaneous transformation of oxyhemoglobin in the solution tomethemoglobin, a physiologically inactive form of hemoglobin which doesnot function as a blood substitute by releasing oxygen into a patient'sbloodstream. To improve shelf life, the blood substitutes industrydelays loss of function by refrigerating or freezing the solutions, orcontrolling the oxygenation state of the hemoglobin within the solution.

Therapeutic hemoglobin solutions are typically oxygenated, stored frozenin conventional oxygen-permeable, 200 ml plastic solution bags, andthawed to room temperature hours before use.

WO 99/15289 describes a multiple layer structure for fabricating medicalproducts. The layer structure has a core layer of an ethylene vinylalcohol copolymer, a solution contact layer of a polyolefin positionedon a first side of the core layer, an outer layer positioned on a secondside of the core layer opposite the solution contact layer, the outerlayer being selected from the group consisting of polyamides, polyestersand polyolefins, and a tie layer on each side of the core layer. The tielayer is 0.2–1.2 mils in thickness, and is the only layer of thestructure which may be composed of ethylene vinyl acetate.

U.S. Pat. No. 6,271,351 describes a method of storing deoxyhemoglobin ina container which is said to exhibit low oxygen permeability. Thecontainer is composed of a layered structure including ethylene vinylalcohol, but does not include ethylene vinyl acetate.

There is a need for containers having minimal oxygen permeability whichwould enable deoxygenated hemoglobin solutions to be stored for weeks ormonths at room temperature and then used as a blood substitute.

Receptacles used for the shipping, storing, and delivery of liquids,such as medical or therapeutic fluids, are often fabricated fromsingle-ply or multiple-ply polymeric materials. Two sheets of thesematerials are placed in overlapping relationship and the overlappingsheets are bonded at their outer peripheries to define a chamber orpouch for containing liquids. It is also possible to extrude thesematerials as a tube and to seal longitudinally spaced portions of thetube to define chambers between two adjacent seals. Typically, thematerials are joined along their inner surfaces using bonding techniquessuch as heat sealing, radio-frequency sealing, thermal transfer welding,adhesive sealing, solvent bonding, sonic sealing, and laser welding.

It is also common to provide such receptacles with access ports toprovide access to the interior of the receptacle. Access ports typicallytake the form of one or more end ports (transfer tubes) inserted betweenthe sidewalls of the receptacle or panel ports attached to a sidewall ofthe receptacle. The end ports typically have a fluid passageway with aclosure wall positioned inside the passageway to form a fluid tight sealof the receptacle. The closure, typically in the form of a membrane,must be punctured by an access needle or “spike” to allow for deliveryof the contents of the receptacle.

Conventional flexible solution receptacles employing end port designstypically use flexible PVC or soft polyolefins such as LDPE to constructthe port tubes. Such materials have sufficient elasticity to grip theoutside of an access spike to retain the spike during fluid delivery.The inner diameter of the end ports are dimensioned to be smaller thanthe outer diameter of the access device. Due to the ductility of PVC orLDPE, the port tube can expand about the outside of the access spike toform an interference fit therewith. However, such receptacle and portclosure systems are readily permeated by oxygen and other gases such ascarbon dioxide. If such receptacles are to be utilized to house a gassensitive liquid, such packages must utilize a gas barrier overwrapmaterial.

To provide a stand-alone gas barrier primary receptacle, all componentsof the receptacle system should be fabricated using barrier material.For medical applications where such receptacles are typically disposedof by incineration, it is desirable to construct the receptacle systemcomponents from non-halogen containing polymers. Halogen containingcompounds have the potential for creating inorganic acids uponincineration. Further, for medical applications, it is also desirable toconstruct the receptacle system components from polymers having a lowquantity of low molecular weight additives, such as plasticizers, assuch low molecular weight components can potentially leach out into thefluids contained or transported therein.

It is well known that certain materials provide a high resistance to theingress of oxygen or other gases. For example, ethylene vinyl alcohol(EVOH) provides a high barrier to the ingress of oxygen. However, EVOHprovides a significant design challenge for use in flexible receptaclesystems as EVOH is also know to be a very rigid material. A port tubecontaining a significant quantity of EVOH will have insufficientelasticity to expand around an access device. Thus, such an EVOHcontaining port tube cannot be dimensioned to be smaller in diameterthan an access device.

Due to the variation in the outer diameter dimensions of access devicescommercially, it is also difficult to design a single port tube to havean appropriate diameter to form an interference fit with all accessdevices commercially available. The spike holder or needle holder hassufficient elasomeric properties to form around an access device andform a grasping hold of the access device. The present invention isprovided to solve these and other problems.

SUMMARY OF THE INVENTION

The present invention provides a receptacle for a therapeutic fluidsusceptible to deterioration on exposure to a gas such as oxygen orcarbon dioxide. The receptacle has walls of sheet material eachincluding at least one layer forming a barrier essentially impermeableto said gas, and a seal sealing the walls together in a region thereof.A transfer tube is sealed in the seal having a proximal end in thereceptacle, a distal end accessible from outside the receptacle, a flowpassage extending between said proximal and distal ends, and a closureblocking flow through said flow passage adapted to be pierced by atubular needle for transfer of therapeutic through the needle. Thetransfer tube and closure are essentially impermeable to said gas.

The present invention further provides a transfer tube for attachment toa receptacle adapted to hold a fluent therapeutic susceptible todeterioration on exposure to gas such as oxygen or carbon dioxide. Thetransfer tube has a tubular body having a proximal end, a distal endopposite the proximal end, a flow passage extending between saidproximal and distal ends adapted to communicate with said receptacle,and a closure blocking flow through the flow passage and adapted to bepierced by a tubular needle for transfer of therapeutic through theneedle. The tubular body and closure are essentially impermeable to saidgas.

The present invention is also directed to a needle holder forapplication to the distal end of a transfer tube of a receptacleparticularly adapted to hold a fluent therapeutic susceptible todeterioration on exposure to gas such as oxygen or carbon dioxide. Theneedle holder is adapted to hold in place the carrier of a transferneedle with the needle piercing the transfer tube. The holder has a bodyhaving a first annular wall defining a first cavity at a first end ofthe body, a second annular wall defining a second cavity at a second endof the body, and a flow passage extending between the two cavities, thefirst annular wall being sized for an interference fit with saidtransfer tube to releasably attach the needle holder to the transfertube, and the second annular wall being sized for an interference fitwith said needle carrier to releasably attach the needle carrier to theneedle holder in a position in which needle is disposed in said flowpassage.

Additional features, advantages, and other aspects and attributes of thepresent invention will be discussed with reference to the followingdrawings and accompanying specification.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 a is a plan view of a flowable materials receptacle and closuresystem;

FIG. 1 b is a cross-sectional view taken along line b—b of FIG. 1 a;

FIG. 1 c is a plan view of a flowable materials receptacle having a fillport and an administration port;

FIG. 2 a is a cross-sectional view of a three-layer tubing;

FIG. 2 b is a cross-sectional view of a two-layer tubing;

FIG. 3 a is a cross-sectional view of a two-layer membrane film;

FIG. 3 b is a cross-sectional view of a three-layer membrane film;

FIG. 3 c is a cross-sectional view of a five-layer membrane film;

FIG. 4 is a cross-sectional view of a membrane film and tube assembly;

FIG. 5 is a side view of a needle or “spike” holder;

FIG. 6 is cross-sectional view of the spike holder of FIG. 6;

FIG. 7 is an cross-sectional view taken along line A—A of FIG. 6;

FIG. 8 is an assembly of the membrane film and tube assembly with thespike holder or needle holder of FIG. 5 with a spike being introducedtherein; and

FIG. 9 is a cross-sectional view of a four-layer membrane film.

DETAILED DESCRIPTION OF THE INVENTION

While this invention is susceptible of embodiments in many differentforms, there is shown in the drawings and will herein be described indetail preferred embodiments of the invention with the understandingthat the present disclosure is to be considered as an exemplification ofthe principles of the invention and is not intended to limit the broadaspect of the invention to the embodiments illustrated.

FIG. 1 a shows a flowable materials receptacle and closure systemgenerally referred to as 10. The system includes a flowable materialsreceptacle 30, a port (transfer) tube and closure assembly 40, and aneedle or “spike” holder 50. The relative size of the receptacle 30,assembly 40, and spike holder 50 are exaggerated for illustrativepurposes. In a preferred form of the invention, the system 10 is usefulfor containing and delivering a fluent therapeutic susceptible todeterioration on exposure to a gas such as oxygen or carbon dioxide. Thesystem is also particularly well suited for storage and delivery of abuffered solution.

What is meant by “flowable material” is a material that will flow by theforce of gravity. Flowable materials therefore include both liquid itemsand powdered or granular items and the like. Flowable materialsreceptacles find particular use for storage and delivery of medical ortherapeutic fluids and include, but are not limited to, I.V.receptacles, peritoneal dialysis drain and fill receptacles, bloodreceptacles, blood product receptacles, blood substitute receptacles,nutritional receptacles, food receptacles and the like.

FIGS. 1 a and 8 illustrate the assembly 40 as including a port(transfer) tube 52 and a closure in the form of a wall or membrane 54.The port tube 52 defines a fluid flow passage 56 and has an end surface58. The membrane 54 is shown attached to the port tube end surface 58.It is contemplated by the present invention the membrane 54 could alsobe positioned inside the port tube flow passage 56 without departingfrom the scope of the present invention.

While it is contemplated the port tube 52 can have any number of layers,in a preferred form of the invention the port tube 52 will includeeither a discrete layer of a barrier material or a blend layer includinga barrier material. The barrier material will present a barrier to thepassage of gasses or water vapor transmission, and, in a preferred formof the invention, will reduce the passage rate of oxygen therethrough.It is also desirable that all materials in the solution contact layer,and more preferably all materials used in the tubing, be free ofhalogens, plasticizers or other low-molecular weight or water solublecomponents that can leach out into the solutions transferred through thetubing. Suitable barrier materials include ethylene vinyl alcoholcopolymers having an ethylene content of from about 25% to about 45% bymole percent, more preferably from about 28% to about 36% by molepercent and most preferably from about 30% to about 34% by mole percent.

In an even more preferred form of the invention, the port tube 52 willhave multiple layers. FIG. 2 a and FIG. 2 b show respectively athree-layer port tube 52 and a two-layer port tube. The three-layer porttube 52 has an outside or an outermost layer 60, a core layer 62 and aninside solution contact layer 64. Similarly, the two-layer port tube 52has an outside layer 60 and an inside, solution contact layer 64.

In a preferred form of the invention, the multiple layer transfer tubeor port tube 52 will have a discrete layer of a barrier material withthe remaining layers being selected from polyolefins. The layers of thetube can be positioned in any order, however, in a preferred form of theinvention, the barrier layer is not positioned as the outside layer 60.Thus, the layers of a three layer tube can be positioned in one of sixorders selected from the group: first/second/third, first/third/second,second/first/third, second/third/first, third/first/second, andthird/second/first. Further, in tube embodiments having more than twolayers, the tube 52 can be symmetrical or asymmetrical from a materialaspect and from a thickness of layers aspect.

Suitable polyolefins include homopolymers, copolymers and terpolymersobtained using, at least in part, monomers selected from α-olefinshaving from 2 to 12 carbons. One particularly suitable polyolefin is anethylene and α-olefin interpolymer (which sometimes shall be referred toas a copolymer). Suitable ethylene and α-olefin interpolymers preferablyhave a density, as measured by ASTM D-792 of less than about 0.915 g/ccand are commonly referred to as very low density polyethylene (VLDPE),ultra low density ethylene (ULDPE) and the like. The α-olefin shouldhave from 3–17 carbons, more preferably from 4–12 and most preferably4–8 carbons. In a preferred form of the invention, the ethylene andα-olefin copolymers are obtained using single site catalysts. Suitablesingle site catalyst systems, among others, are those disclosed in U.S.Pat. Nos. 5,783,638 and 5,272,236. Suitable ethylene and α-olefincopolymers include those sold by Dow Chemical Company under the AFFINITYtrademark, Dupont-Dow under the ENGAGE trademark and Exxon under theEXACT and PLASTOMER trademarks.

The polyolefins also include modified polyolefins and modified olefinsblended with unmodified olefins. Suitable modified polyolefins aretypically polyethylene or polyethylene copolymers. The polyethylenes canbe ULDPE, low density (LDPE), linear low density (LLDPE), medium densitypolyethylene (MDPE), and high density polyethylenes (HDPE). The modifiedpolyethylenes may have a density from 0.850–0.95 g/cc. The polyethylenemay be modified by grafting or otherwise chemically, electronically orphysically associating a group of carboxylic acids, and carboxylic acidanhydrides. Suitable modifying groups include, for example, maleic acid,fumaric acid, itaconic acid, citraconic acid, allylsuccinic acid,cyclohex-4-ene-1,2-dicarboxylic acid,4-methylcyclohex-4-ene-1,2-dicarboxylic acid,bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid,x-methylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid, maleicanhydride, itaconic anhydride, citraconic anhyride, allylsuccinicanhydride, citraconic anhydride, allylsuccinic anhydride,cyclohex-4-ene-1,2-dicarboxylic anhydride,4-methylcyclohex-4-ene-1,2-dicarboxylic anhydride,bicyclo[2.2.1]hept-5-ene2,3-dicarboxylic anhydride, andx-methylbicyclo[2.2.1]hept-5-ene-2,2-dicarboxylic anhydride.

Examples of other modifying groups include C₁–C₈ alkyl esters orglycidyl ester derivatives of unsaturated carboxylic acids such asmethyl acrylate, methyl methacrylate, ethyl acrylate, ethylmethacrylate, butyl acrylate, butyl methacrylate, glycidyl acrylate,glycidal methacrylate, monoethyl maleate, diethyl maleate, monomethylmaleate, diethyl maleate, monomethyl fumarate, dimethyl fumarate,monomethyl itaconate, and diethylitaconate; amide derivatives ofunsaturated carboxylic acids such as acrylamide, methacrylamide,maleicmonoamide, maleic diamide, maleic N-monoethylamide, maleicN,N-dietylamide, maleic N-monobutylamide, maleic N,N dibutylamide,fumaric monoamide, fumaric diamide, fumaric N-monoethylamide, fumaricN,N-diethylamide, fumaric N-monobutylamide and fumaric N,N-dibutylamide;imide derivatives of unsaturated carboxylic acids such as maleimide,N-butymaleimide and N-phenylmaleimide; and metal salts of unsaturatedcarboxylic acids such as sodium acrylate, sodium methacrylate, potassiumacrylate and potassium methacrylate. More preferably, the polyolefin ismodified by a fused ring carboxylic anhydride and most preferably amaleic anhydride.

The polyolefins also include ethylene vinyl acetate copolymers, modifiedethylene vinyl acetate copolymers and blends thereof. The modified EVAhas an associated modifying group selected from the above listedmodifying groups.

In one preferred form of the invention, the tube 52 has a solutioncontact layer 64 of a modified EVA copolymer sold by DuPont Packagingunder the trademark BYNEL® CXA, a core layer 62 of an EVOH and anoutside layer 60 of a modified EVA, again preferably CXA. Such astructure is symmetrical from a materials standpoint. According to apreferred form of the invention, such tubing will have layers of thefollowing thickness ranges: outside layer 60 from about 0.002 inches toabout 0.042 inches, preferably about 0.010 inches, the core layer 62from about 0.016 inches to about 0.056 inches, preferably about 0.039inches, and the solution contact layer 64 of from about 0.002 inches toabout 0.042 inches, preferably about 0.010 inches.

In another preferred form of the invention, the tube 52 has a solutioncontact layer 64 of an EVOH, a core layer 62 of a modified EVA andpreferably BYNEL® CXA and an outside or outermost layer 60 of anethylene and α-olefin copolymer. Such a structure is symmetrical from amaterials standpoint. The tube layers can have various relativethicknesses. According to a preferred form of the invention, tube 52will have layers of the following thickness ranges: outside layer 60from about 0.002 inches to about 0.042 inches; the core layer 62 fromabout 0.002 inches to about 0.042 inches; and the solution contact layer64 from about 0.016 inches to about 0.056 inches. The outermost layer 60of EVA is well suited for bonding to the transfer tube, especially uponheat sealing.

In a further preferred form, the tube 52 has a solution contact layer 64of BYNEL® CXA, a core layer 62 of EVOH, and an outside layer 60 of ablend of 50% ULDPE and 50% CXA. Such tubing will have layers of thefollowing thickness ranges: outside layer 60 from about 0.002 inches toabout 0.042 inches, preferably about 0.010 inches; the core layer 62from about 0.016 inches to about 0.056 inches, preferably about 0.039inches; and the solution contact layer 64 of from about 0.002 inches toabout 0.042 inches, preferably about 0.010 inches.

In a preferred form of the invention, the port tube 52 shall have thefollowing dimensions: inside diameter from about 0.100 inches to about0.500 inches and the wall thickness shall be from about 0.020 inches toabout 0.064 inches. The port tube 52 can be prepared by injectionmolding, extrusion, coextrusion or other polymer processing techniqueswell known in the art.

Turning our attention now to the closure 54, the membrane film formingthe closure 54 can have any number of layers, but in a preferred form ofthe invention has multiple layers. The membrane film 54, in a preferredform of the invention, shall have a barrier layer as defined above. FIG.3 a shows a two-layer structure 54 having an outside layer 72 and aninside layer 70. FIG. 3 b shows a three-layer structure 54 having anoutside layer 72, an inside layer 70 and a core layer 74. FIG. 3 c showsa five-layer structure 54 having an outside layer 72, an inside layer70, a core layer 74, and two tie layers 76. In a preferred form of theinvention, one layer shall be of a barrier material defined above andthe remaining layer or layers shall be selected from the polyolefinsdefined above, polyamides and polyesters. One of the inside layer 70 oroutside layer 72 shall define a tubing contact layer or seal layer.

Suitable polyamides include those obtained from a ring-opening reactionof lactams having from 4–12 carbons. This group of polyamides thereforeincludes, but is not limited to, nylon 6, nylon 10 and nylon 12.

Acceptable polyamides also include aliphatic polyamides resulting fromthe condensation reaction of di-amines having a carbon number within arange of 2–13, aliphatic polyamides resulting from a condensationreaction of di-acids having a carbon number within a range of 2–13,polyamides resulting from the condensation reaction of dimer fattyacids, and amide containing copolymers. Thus, suitable aliphaticpolyamides include, for example, nylon 66, nylon 6,10 and dimer fattyacid polyamides.

Suitable polyesters include polycondensation products of di- orpolycarboxylic acids and di or poly hydroxy alcohols or alkylene oxides.Preferably, the polyesters are a condensation product of ethylene glycoland a saturated carboxylic acid such as ortho or isophthalic acids andadipic acid. More preferably the polyesters includepolyethyleneterephthalates produced by condensation of ethylene glycoland terephthalic acid; polybutyleneterephthalates produced by acondensations of 1,4-butanediol and terephthalic acid; andpolyethyleneterephthalate copolymers and polybutyleneterephthalatecopolymers which have a third component of an acid component such asphthalic acid, isophthalic acid, sebacic acid, adipic acid, azelaicacid, glutaric acid, succinic acid, oxalic acid, etc.; and a diolcomponent such as 1,4-cyclohexanedimethanol, diethyleneglycol,propyleneglycol, etc. and blended mixtures thereof.

In a preferred form of the invention, the membrane structure shall havefive layers as shown in FIG. 3 c and is described in detail in commonlyassigned U.S. Pat. No. 6,083,587 which is incorporated herein byreference and made a part hereof. The outside layer 72 is a polyamideand preferably nylon 12, the two tie layers 76 are a modified EVAcopolymer, the core layer 74 is an EVOH and the inner layer 70 is amodified EVA. In a preferred form of the invention the inside layer 70defines the tubing contact layer.

Further, the structure shown in FIG. 3 c has the following layerthickness ranges: outside layer 72 from about 0.0005 inches to about0.003 inches; the tie layers 76 from about 0.0005 inches to about 0.02inches; the core layer 74 of from about 0.0005 inches to about 0.0015inches; and an inside layer 70 of from about 0.008 inches to about 0.012inches.

In another preferred form, the membrane structure has four layers asshown in FIG. 9. FIG. 9 shows a membrane 126 having an outer layer 128of a polyamide, preferably nylon and more preferably a nylon 12, a thirdlayer 130 of a modified ethylene vinyl acetate, preferably CXA, a secondlayer 132 of a barrier material, preferably EVOH, and an inner solutioncontact layer 134 of a modified ethylene vinyl acetate, preferably CXA.

The outer layer 128 has a thickness of a range of about 0.0003 to 0.0007inches, and preferably about 0.0005 inches. The third layer 130 has athickness range of between 0.0003 to 0.0007 inches, and preferably about0.0005 inches. The second layer 132 has a thickness range of between0.0007 to 0.0013 inches, and preferably about 0.001 inches. The innerlayer 134 has a thickness of between 0.006 and 0.01 inches, andpreferably about 0.008 inches. The membrane film can be formed byextrusion, coextrusion, lamination, extrusion coating, orother polymerprocessing technique well known in the art.

Turning our attention now to the receptacle 30 (FIGS. 1 a, 1 b and 1 c).In a preferred form of the invention the receptacle 30 is of a polymericmaterial or structure and more preferably includes a barrier material asan additive to a layer or as a discrete barrier layer as defined above.In a preferred form of the invention, the receptacle has sidewalls 80which are positioned in registration and sealed along a peripheral seam82. The sealing can be carried out by conductive heat sealing orinductive heat sealing such as through radio frequency sealing or can besealed by other methods well known in the art. The peripheral seam 82,preferably, has an outer seal 84, an inner seal 86 and a material depot88 positioned therebetween. One or more access or administration ports89 can be provided as is well known in the art. In a preferred form ofthe invention the recepatacle can have a fill port 89′ on one end of thecontainer and a administration port 89 on an opposite end of thecontainer. The administration port can be the closure assembly 40described above. The fill port 89′ can have the same structure as theadministration port or, in a more preferred form of the invention, willbe of a polyolefin material, a polyolefin blend or one of the othermaterials set forth above but will not include the gas barrier materialof the administration port. The fill port 89′ can be removed afterfilling the container by a hot knife or during a step of sealing thecontainer after filling. The material depot 88 defines an unsealedportion where material from the seals 84 and 86 can flow. The sidewalls80 define a fluid containing chamber 90. The fluid chamber is capable ofstoring flowable materials and more preferably is capable of forming afluid tight seal. The receptable and closure assembly will preferablyhave an oxygen permeability of less than 0.10 cc/day, more preferablyless than 0.075 cc/day and most preferably less than 0.04 cc/day, or anyrange or combination of ranges therein.

In a preferred form of the invention, the sidewalls 80 are of a multiplelayer structure and can include the material structures as shown inFIGS. 3 a to 3 c and the description set forth above for thesestructures. In a preferred form of the invention, the sidewall 80 hasfive layers. The structure is the same as that disclosed in FIG. 3 c butincludes an additional layer outward from inside layer 70. The innerlayer is preferably a polyolefin and more preferably an ethylene andα-olefin copolymer. The relative thicknesses of the layers is fully setforth in U.S. Pat. No. 6,083,587 at column 5, line 64 through column 6,line 8.

The receptacle 30 shall have the following physical properties: modulusof elasticity of the sidewall of the receptacle is less than 60,000 psiand more preferably less than 40,000 psi; is suitable of storing anoxygen sensitive composition for at least about 6 months, morepreferably at least about 1 year, more preferably at least about 2 yearsand even more preferably at least about 3 years; is capable of achievingthese storage periods at temperatures of about room temperature and morepreferably from 5° C. to about 45° C.

Turning our attention now to FIG. 4 showing a port tube/closure assembly40. The assembly 40 preferably is constructed without the use ofsolvents or adhesives. The assembly 40 has one of the closure 54described above formed into a disk shape and attached to the port tubeend surface 58. The closure can also be attached inside the port tubeflow passage 56. The closure 54 can be placed in contact with the endsurface 58 of the port tube and attached thereto using conductive heatsealing, inductive heat sealing (such as using radio frequencyenergies), ultrasonic welding, vibration welding, or other techniqueswell known in the art.

It should be understood that a port tube 52 having any of theconstructions described above can be combined with a closure 54 havingany of the constructions described above. Thus, an assembly of a porttube 52 having any number of layers and a closure 54 having two layers,three layers or more is contemplated by the present invention. It isalso contemplated that a port tube 52 having two layers, three layers ormore could be combined with a membrane film 54 having any number oflayers.

The spike holder 50 (which also may be referred to as a needle holder)is shown in FIGS. 1 a, and 5–8. The spike holder 50 has a body 100having a first annular wall defining a first cavity or chamber 110 at afirst end of the body, a second annular wall defining a second cavity ora second chamber 112 at a second end of the body, and a flow passage 114connecting the first and second chambers. The first chamber 110 isdimensioned to telescopically receive an end portion 116 of the porttube 52. In a preferred form of the invention the spike holder isfixedly attached to the port tube but could be releasably attachedwithout departing from the scope of the present invention. It iscontemplated by the present invention the annular wall could extend intothe port tube flow passage 56 and attach thereto without departing fromthe present invention. The second chamber 112 is dimensioned to have aninterference fit with an access spike or transfer needle 117 describedbelow. As noted herein, the term interference fit means that the secondchamber 112 has an identical or smaller dimension than the spike holdersinserted therein but is capable of deforming (e.g., elastically) aroundthe insert to hold the inserted device by friction. It is contemplatedthe second chamber 112 will fixedly attach to the insert or releasablyattach to the insert. In a preferred form of the invention, the firstchamber 110 and the second chamber 112 have a generally circularcross-sectional shape, the first chamber 110 having a first diameter andthe second chamber 112 having a second diameter, the first diameterbeing larger than the second diameter.

In a preferred form of the invention, the spike holder 50 has anoutwardly extending flange 118 at an intermediate portion thereof. Theflange 118 is positioned generally at the intersection of the firstchamber 110 and the second chamber 112. The flange 118 has a firstsurface 120 which is textured to facilitate handling and manipulation ofthe holder. In one embodiment, this texture is provided by a pluralityof buttresses 122 around the first annular wall of the body 100. In apreferred form of the invention, the flange 118 is generally circular incross-sectional shape and the buttresses 122 are circumferentiallyspaced about the first surface 120. The buttresses are shown having agenerally tear-drop shape, however, they could be of numerous differentshapes without departing from the present invention. The buttresses areprovided to form a gripping surface for those handling the spike holder50. It may also be desirable to add an internal shoulder or otherfeature to the spike holder 50 to limit the extent the transfer tube canbe inserted into the flow passage.

The spike holder 50 is formed from a polyolefin as defined above andmore particularly is an ethylene and α-olefin copolymer. The spikeholder 50 can also have a textured or matte finish on a portion or theentire outer surface 124 of the holder 50 for ease of handling. Thespike holder 50 can be formed by any suitable polymer forming techniqueknown to those skilled in the art and preferably the spike holder 50 isformed by injection molding. The spike holder 50 can also include amembrane film 54′ positioned in the passageway 114 in lieu of or inaddition to the membrane 54.

In a preferred form of the invention, the spike holder 50 is formeddirectly over the end portion 116 of the port tube/membrane filmassemblies 40 described above. Such a process is conventional andreferred to as an overmolding process. The overmolding process includesthe steps of: (1) providing a tubing as set forth above; providing amold for forming a spike holder; inserting a portion 116 of the tubing52 into the mold; and supplying polymeric material to the mold to form aspike holder on the tubing.

In an embodiment of the invention, the tubing, closure, and/or containersidewalls are comprised of a multilayer polymeric structure whichincludes a first layer of an ethylene vinyl alcohol copolymer havingfirst and second sides, and a second layer of a modified ethylene vinylacetate copolymer attached to the first side of the first layer. Thesecond layer has a thickness of greater than 1.2 mils, preferably atleast 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5,2.6, 2.7, 2.8, 2.9, or 3.0 mils. The polymeric structure optionallyincludes a third layer attached to the second side of the first layer.Preferably, the third layer comprises a polyamide or polyester asdescribed herein. In one embodiment, the sidewalls of a containerinclude a core layer, outside layer, or solution contact layercomprising a modified ethylene vinyl acetate copolymer as describedherein. In another embodiment, the polymeric structure comprises anoutside layer of a polyamide or polyester, a core layer of an ethylenevinyl alcohol copolymer, and a sealing layer of a modified ethylenevinyl acetate copolymer, wherein the core layer is between the outsideand sealing layers. This polymeric structure optionally includes one ormore tie layers attached to the core layer.

The receptacles of the present invention are used to storedeoxyhemoglobin solutions or other therapeutic fluids which react withoxygen. The receptacles are filled with the solution in a low oxygen oroxygen free environment, sealed, and then stored at about 5 to 45° C.for weeks or months prior to use. Conventional methods of filling andsealing containers in a low oxygen or oxygen free environment aresuitable for the invention. After storage, the deoxyhemoglobin solutioncontains less than 15% methemoglobin and is physiologically acceptablefor administration to a patient. In a preferred embodiment, thedeoxyhemoglobin solutions are stored at room temperature and ambientconditions.

The following is an example of the present invention and is not intendedto limit the claims of the present invention.

EXAMPLE

Several 250 ml volume receptacles were fabricated as shown in FIG. 1 cwith a fill port and an administration port. Each receptacles had atotal nominal surface area of approximately 450 cm². The administrationport had a core layer of an EVOH and an outside layer of a modified EVA(CXA) and a solution contact layer of a modified EVA (CXA). A membranefilm was sealed to a distal end of the administration port. The membranehad an outer layer 134 of nylon 12, a third layer 130 of a modifiedethylene vinyl acetate (CXA), a second layer 132 of EVOH, and an innersolution contact layer 128 of a modified ethylene vinyl acetate (CXA)(see FIG. 9). The fill port was injection molded of ethylene vinylacetate (EVA). The receptacle sidewalls were fabricated from afive-layer structure as shown in FIG. 3 c. An outside layer 72 was nylon12, two tie layers 76 were a modified EVA copolymer (CXA), a core layer74 was an EVOH and the inner layer 70 was a metallocene catalyzed ultralow density polyethylene. The empty containers were sterilized byexposure to gamma radiation. The sterile containers were asepticallyfilled with an oxygen sensitive indicator solution through the fill portand the fill port was sealed and removed by a heated bar. The oxygenpermeability of the containers were measured at 70% relative humidity attemperatures of 4° C., 23° C. and 40° C. and found to be 0.0008, 0.0041,and 0.0396 cc/day/package, respectively.

It is understood that, given the above description of the embodiments ofthe invention, various modifications may be made by one skilled in theart. Such modifications are intended to be encompassed by the claimsbelow.

1. A receptacle for a medical fluid susceptible to deterioration onexposure to a gas such as oxygen or carbon dioxide, said receptaclecomprising: walls of sheet material each including at least one layerforming a barrier essentially impermeable to said gas; a seal sealingthe walls together in a region thereof; a transfer tube sealed in theseal having a proximal end in the receptacle, a distal end accessiblefrom outside the receptacle, a flow passage extending between saidproximal and distal ends, the tube having a layer including an ethylenevinyl alcohol copolymer; and a closure blocking flow through said flowpassage adapted to be pierced by a tubular needle for transfer ofmedical fluid through the needle, said transfer tube and closure beingessentially impermeable to said gas.
 2. A receptacle as set forth inclaim 1 wherein said closure is attached to a distal end surface of thetransfer tube.
 3. A receptacle as set forth in claim 2 wherein theclosure is a multiple layer polymeric structure.
 4. A receptacle as setforth in claim 3 wherein the multiple layer polymeric structurecomprises: a first layer of an ethylene vinyl alcohol copolymer having afirst side and a second side; and a second layer of a modified ethylenevinyl acetate copolymer attached to the first side of the first layer.5. A receptacle as set forth in claim 4 further comprising a third layerattached to the second side of the first layer.
 6. A receptacle as setforth in claim 5 wherein the third layer is selected from the groupconsisting of polyamides and polyesters.
 7. A receptacle as set forth inclaim 6 wherein the polyamides are aliphatic polyamides obtained fromthe condensation reaction of di-amines having a carbon number within arange of 2–13, aliphatic polyamides resulting from a condensationreaction of di-acids having a carbon number within a range of 2–13,polyamides resulting from the condensation reaction of dimer fattyacids, and amide containing copolymers.
 8. A receptacle as set forth inclaim 7 wherein the polyamide is obtained from a ring-opening reactionof a lactam.
 9. A receptacle as set forth in claim 4 wherein themodified ethylene vinyl acetate copolymer has a modifying group selectedfrom the group consisting of: carboxylic acid and carboxylic acidanhydrides.
 10. A receptacle as set forth in claim 9 wherein themodifying group is selected from the group consisting of: maleic acid,fumaric acid, itaconic acid, citraconic acid, allylsuccinic acid,cyclohex-4-ene-1,2-dicarboxylic acid,4-methylcyclohex-4-ene-1,2-dicarboxylic acid,bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid,x-methylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid, maleicanhydride, itaconic anhydride, citraconic anhyride, allylsuccinicanhydride, citraconic anhydride, allylsuccinic anhydride,cyclohex-4-ene-1,2-dicarboxylic anhydride,4-methylcyclohex-4-ene-1,2-dicarboxylic anhydride,bicyclo[2.2.1]hept-5-ene2,3-dicarboxylic anhydride, andx-methylbicyclo[2.2.1]hept-5-ene-2,2-dicarboxylic anhydride, methylacrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, butylacrylate, butyl methacrylate, glycidyl acrylate, glycidal methacrylate,monoethyl maleate, diethyl maleate, monomethyl maleate, diethyl maleate,monomethyl fumarate, dimethyl fumarate, monomethyl itaconate, anddiethylitaconate; amide derivatives of unsaturated carboxylic acids suchas acrylamide, methacrylamide, maleicmonoamide, maleic diamide, maleicN-monoethylamide, maleic N,N-dietylamide, maleic N-monobutylamide,maleic N,N dibutylamide, fumaric monoamide, fumaric diamide, fumaricN-monoethylamide, fumaric N,N-diethylamide, fumaric N-monobutylamide andfumaric N,N-dibutylamide; imide derivatives of unsaturated carboxylicacids such as maleimide, N-butymaleimide and N-phenylmaleimide; andmetal salts of unsaturated carboxylic acids such as sodium acrylate,sodium methacrylate, potassium acrylate and potassium methacrylate. 11.A receptacle as set forth in claim 10 wherein the modifying group is afused ring carboxylic acid anhydride.
 12. A receptacle as set forth inclaim 4 wherein the second layer is positioned between the first layerof ethylene vinyl alcohol and the end of the tubing.
 13. A receptacle asset forth in claim 12 wherein the ethylene vinyl alcohol copolymer hasan ethylene content of from about 25% to about 45% by mole percent. 14.A receptacle as set forth in claim 12 wherein the ethylene vinyl alcoholcopolymer has an ethylene content of from about 28% to about 36% by molepercent.
 15. A receptacle as set forth in claim 12 wherein the ethylenevinyl alcohol copolymer has an ethylene content of from about 30% toabout 34% by mole percent.
 16. A receptacle as set forth in claim 1having a needle holder on the distal end of the transfer tube.
 17. Areceptacle as set forth in claim 16 wherein said layers comprise aninside layer of heat sealable material having an inner face and an outerface, said barrier layer being superposed on the outer face of saidinside layer.
 18. The receptacle as set forth in claim 16 wherein saidbarrier layer comprises ethylene vinyl alcohol.
 19. A receptacle as setforth in claim 1 wherein each of said walls comprises multiplesuperposed layers at least one of which constitutes said barrier layer.20. A receptacle as set forth in claim 1 wherein said transfer tubecomprises multiple superposed layers comprising: a first layer ofethylene vinyl alcohol copolymer; a second layer; a third layer; whereinthe second layer and the third layer each being selected from the groupconsisting of: (1) ethylene and α-olefin interpolymers having a densityof less than about 0.915 g/cc, (2) ethylene vinyl acetate copolymers,and (3) modified ethylene vinyl acetate copolymers; and wherein thefirst layer, the second layer and the third layer are concentricallydisposed with respect to one another.
 21. A receptacle as set forth inclaim 20 wherein the second layer is a first α-olefin interpolymer. 22.A receptacle as set forth in claim 21 wherein the third layer is amodified ethylene vinyl acetate copolymer.
 23. A receptacle as set forthin claim 22 wherein the modified ethylene vinyl acetate copolymer has amodifying group selected from carboxylic acid and carboxylic acidanhydrides.
 24. A receptacle as set forth in claim 23 wherein themodifying group is selected from the group consisting of: maleic acid,fumaric acid, itaconic acid, citraconic acid, allylsuccinic acid,cyclohex-4-ene-1,2-dicarboxylic acid,4-methylcyclohex-4-ene-1,2-dicarboxylic acid,bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid,x-methylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid, maleicanhydride, itaconic anhydride, citraconic anhyride, allylsuccinicanhydride, citraconic anhydride, allylsuccinic anhydride,cyclohex-4-ene-1,2-dicarboxylic anhydride,4-methylcyclohex-4-ene-1,2-dicarboxylic anhydride,bicyclo[2.2.1]hept-5-ene2,3-dicarboxylic anhydride, andx-methylbicyclo[2.2.1]hept-5-ene-2,2-dicarboxylic anhydride, methylacrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, butylacrylate, butyl methacrylate, glycidyl acrylate, glycidal methacrylate,monoethyl maleate, diethyl maleate, monomethyl maleate, diethyl maleate,monomethyl fumarate, dimethyl fumarate, monomethyl itaconate, anddiethylitaconate; amide derivatives of unsaturated carboxylic acids suchas acrylamide, methacrylamide, maleicmonoamide, maleic diamide, maleicN-monoethylamide, maleic N,N-dietylamide, maleic N-monobutylamide,maleic N,N dibutylamide, fumaric monoamide, fumaric diamide, fumaricN-monoethylamide, fumaric N,N-diethylamide, fumaric N-monobutylamide andfumaric N,N-dibutylamide; imide derivatives of unsaturated carboxylicacids such as maleimide, N-butymaleimide and N-phenylmaleimide; andmetal salts of unsaturated carboxylic acids such as sodium acrylate,sodium methacrylate, potassium acrylate and potassium methacrylate. 25.A receptacle as set forth in claim 24 wherein the modifying group is afused ring carboxylic acid anhydride.
 26. A receptacle as set forth inclaim 21 wherein the third layer is a second α-olefin interpolymer. 27.A receptacle as set forth in claim 26 wherein the second α-olefin hasfrom 2 to 12 carbons.
 28. A receptacle as set forth in claim 26 whereinthe second α-olefin has from 4 to 8 carbons.
 29. A receptacle as setforth in claim 21 wherein the first α-olefin has from 2 to 12 carbons.30. A receptacle as set forth in claim 21 wherein the first α-olefin hasfrom 4 to 8 carbons.
 31. A receptacle as set forth in claim 21 whereinthe second layer is a first ultra-low density polyethylene.
 32. Areceptacle as set forth in claim 31 wherein the first ultra-low densitypolyethylene is obtained using a catalyst type selected from the groupconsisting of: vanadium, metallocene, single site, Ziegler-Natta andmodified Ziegler-Natta.
 33. A receptacle as set forth in claim 32wherein the catalyst type is metallocene.
 34. A receptacle as set forthin claim 32 wherein the catalyst type is single site.
 35. A receptacleas set forth in claim 1 wherein the transfer tube is relatively rigidand the closure comprises a puncturable wall adjacent the distal end ofthe transfer tube.
 36. A transfer tube for attachment to a receptacleadapted to hold a medical fluid susceptible to deterioration on exposureto gas such as oxygen or carbon dioxide, said transfer tube comprising atubular body having a proximal end, a distal end opposite the proximalend, a flow passage extending between said proximal and distal endsadapted to communicate with said receptacle, and a closure blocking flowthrough the flow passage and adapted to be pierced by a tubular needlefor transfer of medical fluid through the needle, said tubular body andclosure being essentially impermeable to said gas and each having alayer including an ethylene vinyl alcohol copolymer.
 37. A transfer tubeas set forth in claim 36 wherein said transfer tube comprises multiplesuperposed layers comprising: a first layer of ethylene vinyl alcoholcopolymer; a second layer; a third layer; wherein the second layer andthe third layer each being selected from the group consisting of: (1)ethylene and α-olefin interpolymers having a density of less than about0.915 g/cc, (2) ethylene vinyl acetate copolymers, and (3) modifiedethylene vinyl acetate copolymers; and wherein the first layer, thesecond layer and the third layer are concentrically disposed withrespect to one another.
 38. A transfer tube as set forth in claim 37wherein the first α-olefin has from 4 to 8 carbons.
 39. A transfer tubeas set forth in claim 38 wherein the second layer is a first ultra-lowdensity polyethylene.
 40. A transfer tube as set forth in claim 39wherein the first ultra-low density polyethylene is obtained using acatalyst type selected from the group consisting of: vanadium,metallocene, single site, Ziegler-Natta and modified Ziegler-Natta. 41.A transfer tube as set forth in claim 40 wherein the catalyst type issingle site.
 42. A transfer tube as set forth in claim 40 wherein thecatalyst type is metallocene.
 43. A transfer tube as set forth in claim37 wherein the third layer is a second α-olefin interpolymer.
 44. Atransfer tube as set forth in claim 43 wherein the second α-olefin hasfrom 2 to 12 carbons.
 45. A transfer tube as set forth in claim 43wherein the second α-olefin has from 4 to 8 carbons.
 46. A transfer tubeas set forth in claim 37 wherein the third layer is a modified ethylenevinyl acetate copolymer.
 47. A transfer tube as set forth in claim 37wherein the first α-olefin has from 2 to 12 carbons.
 48. A transfer tubeas set forth in claim 37 wherein the second layer is a first α-olefininterpolymer.
 49. A transfer tube as set forth in claim 36 having aneedle holder on the distal end of the tubular body.
 50. A transfer tubeas set forth in claim 49 wherein said tubular body is formed frommultiple superposed layers at least one of which is a barrier layeressentially impermeable to said gas.
 51. A transfer tube as set forth inclaim 36 wherein the tubular body is relatively rigid and the closurecomprises an end wall of puncturable material essentially impermeable tosaid gas on the distal end of the body.
 52. A method for storing amedical fluid susceptible to deterioration on exposure to gas, themethod comprising: providing a container comprising walls of sheetmaterial each including at least one layer forming a barrier essentiallyimpermeable to said gas; a seal sealing the walls together in a regionthereof; a transfer tube sealed in the seal having a proximal end in thecontainer, a distal end accessible from outside the container, a flowpassage extending between said proximal and distal ends, the tube havinga layer including an ethylene vinyl alcohol copolymer; and a closureblocking flow through said flow passage adapted to be pierced by atubular needle for transfer of therapeutic through the needle, saidtransfer tube and closure being essentially impermeable to said gas;filling the container with the medical fluid; and storing the filledcontainer at 5 to about 45 degrees Centigrade for at least about 6months.
 53. The method of claim 52 wherein the medical fluid isdeoxyhemoglobin.
 54. The method of claim 52 wherein the filled containeris stored at room temperature for about one year.
 55. A method forstoring a medical fluid susceptible to deterioration on exposure to gas,the method comprising: providing a container comprising walls of sheetmaterial each including at least one first layer of ethylene vinylalcohol and at least one second layer of modified ethylene vinyl acetatecopolymer, said second layer having a thickness of more than 1.2 mils,and said sheet material forming a barrier essentially impermeable tosaid gas; a seal sealing the walls together in a region thereof; atransfer tube sealed in the seal having a proximal end in the container,a distal end accessible from outside the container, a flow passageextending between said proximal and distal ends; and a closure blockingflow through said flow passage adapted to be pierced by a tubular needlefor transfer of medical fluid through the needle, said transfer tube andclosure being essentially impermeable to said gas; filling the containerwith the medical fluid; and storing the filled container at 5 to about45 degrees Centigrade for at least about 6 months.
 56. A receptacle fora medical fluid susceptible to deterioration on exposure to a gas suchas oxygen or carbon dioxide, said receptacle comprising: walls of sheetmaterial each including at least one first layer of ethylene vinylalcohol and at least one second layer of modified ethylene vinyl acetatecopolymer, said second layer having a thickness of more than 1.2 mils,and said sheet material forming a barrier essentially impermeable tosaid gas; a seal sealing the walls together in a region thereof; atransfer tube sealed in the seal having a proximal end in thereceptacle, a distal end accessible from outside the receptacle, a flowpassage extending between said proximal and distal ends; and a closureblocking flow through said flow passage adapted to be pierced by atubular needle for transfer of medical fluid through the needle, saidtransfer tube and closure being essentially impermeable to said gas.